Clinical Trials /

Varlitinib in Combination With mFOLFOX6 for Advanced or Metastatic Gastric Cancer (First Line)

NCT03130790

Description:

This protocol for Varlitinib is developed for the treatment of Gastric Cancer. Varlitinib (also known as ASLAN001) is a small-molecule, adenosine triphosphate competitive inhibitor of the tyrosine kinases - epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, and HER4. Varlitinib may be beneficial to subjects with cancer by simultaneous inhibition of these receptors. The purpose of this study is to determine the safety and efficacy of Varlitinib in combination with mFOLFOX6 for the treatment of Gastric Cancer. Treatment groups are Varlitinib+mFOLFOX6 and Placebo+mFOLFOX6.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Varlitinib in Combination With mFOLFOX6 for Advanced or Metastatic Gastric Cancer (First Line)
  • Official Title: A Two-Part Phase 2/ 3 Multicentre, Double-Blind, Randomized, Placebo Controlled Study of Varlitinib Plus mFOLFOX6 Verses Placebo Plus mFOLFOX6 In Subjects With HER1/ HER2 Co Expressing Advanced or Metastatic Gastric Cancer Without Prior Exposure to Systemic Therapy

Clinical Trial IDs

  • ORG STUDY ID: ASLAN001-012
  • NCT ID: NCT03130790

Conditions

  • Gastric Cancer

Interventions

DrugSynonymsArms
VarlitinibASLAN001, ARRY-334543, SPS4370, QBT01Varlititib+mFOLFOX6
mFOLFOX6Varlititib+mFOLFOX6
PlaceboPlacebo+mFOLFOX6
mFOLFOX6Placebo+mFOLFOX6

Purpose

This protocol for Varlitinib is developed for the treatment of Gastric Cancer. Varlitinib (also known as ASLAN001) is a small-molecule, adenosine triphosphate competitive inhibitor of the tyrosine kinases - epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, and HER4. Varlitinib may be beneficial to subjects with cancer by simultaneous inhibition of these receptors. The purpose of this study is to determine the safety and efficacy of Varlitinib in combination with mFOLFOX6 for the treatment of Gastric Cancer. Treatment groups are Varlitinib+mFOLFOX6 and Placebo+mFOLFOX6.

Trial Arms

NameTypeDescriptionInterventions
Varlititib+mFOLFOX6Experimental
  • Varlitinib
  • mFOLFOX6
Placebo+mFOLFOX6Placebo Comparator
  • Placebo
  • mFOLFOX6

Eligibility Criteria

        Inclusion Criteria - Phase 2 Part

          1. Subjects of respective country's legal age or older at the time of written informed
             consent.

          2. Subjects with histologically confirmed inoperable locally advanced, recurrent, or
             metastatic adenocarcinoma of the stomach or GEJ cancers may include Siewert Class I,
             II, or III types.

          3. Mandatory provision of an unstained, archived tumor tissue sample in a quantity
             sufficient to allow for local lab analysis of HER1 and HER2 expression status. If
             archived tumor tissue is not available, subject must agree to undergo fresh core
             biopsy to obtain adequate tumor tissue

          4. Subjects with tumors with IHC evidence of expression of HER1 (at level of + or ++ or
             +++) and HER-2 (at level of +, or ++) using standard criteria in the local lab.
             Subjects with HER-2 over expression at level of +++ determined by IHC and subject
             confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by FISH but has
             contradiction to trastuzumab*.

             *For details of contraindication related to trastuzumab, refer to package insert or US
             treatment guideline.

          5. Have radiographically measurable disease as defined by RECIST v1.1

          6. Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

          7. Estimated life expectancy of more than 4 months

          8. Able to swallow and retain oral medication

          9. Subject with adequate organ and hematological function:

             d) Hematological function, as follows: i. Absolute neutrophil count (ANC) ≥1.5 x 109/L
             ii. Platelet count ≥ 100 x 109/L iii. HgB≥9 g/dL (packed red cell blood transfusions
             are not allowed within one week prior to baseline hematology profile).

             e) Renal functions, as follows: i. Serum creatinine ≤1.5x upper limit of normal (ULN)
             or estimated glomerular filtration rate (eGFR)> 60 mL/min/1.73m2 f) Hepatic function,
             as follows: i. Total bilirubin ≤1.5 x ULN ii. AST and ALT ≤2.5 x ULN (or ≤5 x ULN in
             subjects with liver metastasis) iii. Albumin ≥25 g/L

         10. Negative serum human chorionic gonadotropin (HCG)/ or urine pregnancy test within 7
             days prior to randomization for premenopausal women of reproductive capacity and for
             women 12 months after menopause

         11. Willingness to use highly effective birth control method (failure rate <1%) while on
             study.

        Inclusion Criteria - Phase 3 Part

          1. Subjects of respective country's legal age or older at the time of written informed
             consent.

          2. Subjects with histologically confirmed inoperable locally advanced, recurrent, or
             metastatic adenocarcinoma of the stomach or GEJ cancers may include Siewert Class I,
             II, or III types.

          3. Mandatory provision of an unstained, archived tumor tissue sample in a quantity
             sufficient to allow for local lab analysis of HER1 and HER2 expression status. If
             archived tumor tissue is not available, subject must agree to undergo fresh core
             biopsy to obtain adequate tumor tissue.

          4. Subjects with tumors with IHC evidence of expression of HER1 (at level of + or ++ or
             +++) and HER-2 (at level of +, or ++) using standard criteria in the local lab.
             Subjects with HER-2 over expression at level of +++ determined by IHC and subject
             confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by FISH but has
             contradiction to trastuzumab*.

          5. Note: *For details of contraindication related to trastuzumab, refer to package insert
             or US treatment guideline

          6. Subjects with ECOG performance status of 0 to 1

          7. Able to swallow and retain oral medication

          8. Subject with adequate organ and hematological function:

             a) Hematological function, as follows: i. Absolute neutrophil count (ANC) ≥1.5 x 109/L
             ii. Platelet count ≥100 x 109/L iii. HgB≥9 g/dL (packed red cell blood transfusions
             are not allowed within one week prior to baseline hematology profile).

             b) Renal functions, as follows: i. Serum creatinine ≤ 1.5x ULN or eGFR> 60
             mL/min/1.73m2 c) Hepatic function, as follows: i. Total bilirubin ≤1.5 x ULN ii. AST
             and ALT ≤2.5 x ULN (or ≤5 x ULN in subjects with liver metastasis) iii. Albumin ≥25
             g/L

          9. Negative serum human chorionic gonadotropin (HCG)/ or urine pregnancy test within 7
             days prior to randomization for premenopausal women of reproductive capacity and for
             women 12 months after menopause

         10. Willingness to use highly effective birth control method (failure rate <1%) while on
             study.

        Exclusion Criteria:

          1. Subject with HER-2 over expression at level of +++ determined by IHC or subject
             confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by Fluorescence in
             situ hybridization (FISH) in the central lab.

          2. Prior systemic anti-cancer treatment for inoperable locally advanced, recurrent, or
             metastatic adenocarcinoma of the stomach or GEJ. However, previous neo adjuvant
             chemotherapy is allowed if subject has progression of disease more than 6 months after
             neoadjuvant treatment.

          3. Subjects have undergone major surgery within 28 days prior to randomization

          4. Subject with brain lesion, known brain metastases (unless previously treated and well
             controlled for a period of at least 4weeks).

          5. Subject with malabsorption syndrome, diseases significantly affecting gastrointestinal
             function, extensive resection of the stomach or small bowel, or difficulty in
             swallowing and retaining oral medications.

          6. Subjects with an uncontrolled intercurrent illness including, but not limited to,
             ongoing or active infection, New York heart Association class III or IV congestive
             heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia,
             diabetes, hypertension, or psychiatric illness/social situations that would limit
             compliance with study requirements.

          7. Subjects with any history of other malignancy unless in remission for more than 1
             year. (Nonmelanoma skin carcinoma and carcinoma-in-site of uterine cervix treated with
             curative intent is not exclusionary).

          8. Female subjects who are pregnant or breast feeding.

          9. Subjects who were previously treated with varlitinib.

         10. Subjects who took other investigational drugs and/or used investigational medical
             devices or have undergone major surgery within 28 days before initiating varlitinib
             therapy.

         11. Are currently on or have received anti-cancer therapy, radiation or local treatment
             within the past 28 days

         12. Subject with unresolved or unstable serious toxicity (≥ CTCAE 4.03 Grade 2) from prior
             administration of another investigational drug and/or prior cancer treatment(excluding
             hair loss)

         13. Subjects with a known history of human immunodeficiency virus (HIV), decompensated
             cirrhosis, hepatitis B infection with hepatitis B virus DNA exceeding 2000 IU/mL or
             hepatitis C (treatment naïve or after treatment without sustained virologic response).

         14. Known history of drug addiction within the past 1 year.

         15. Subjects who need continuous treatment with proton pump inhibitors during the study
             period.

         16. Any history or presence of clinically significant cardiovascular, respiratory,
             hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic,
             neurologic or psychiatric disease or any other condition which in the opinion of the
             Investigator could jeopardize the safety of the subject or the validity of the study
             results.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:21 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage change from baseline in tumor size at Week 12 - Phase 2 part
Time Frame:At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 3 months)
Safety Issue:
Description:Phase 2 part: Percentage change in tumour size defined as the percentage change from baseline in the sum of longest diameters of target lesions as assessed by ICR and defined by the RECIST v1.1 criteria

Secondary Outcome Measures

Measure:Objective Response Rate (ORR) - Phase 2 part
Time Frame:At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
Safety Issue:
Description:Phase 2 part: Objective Response Rate (ORR) defined as the proportion of subjects with a best objective response (BOR) of complete response (CR) or partial response (PR), as defined by the RECIST v1.1 criteria.
Measure:Progression-free survival (PFS) - Phase 2 part
Time Frame:At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
Safety Issue:
Description:Phase 2 part: Progression-free survival (PFS) defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of disease progression), whichever comes first. Progression is defined in accordance with the RECIST v1.1 criteria.
Measure:Time to response (TTR) - Phase 2 part
Time Frame:At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
Safety Issue:
Description:Phase 2 part: Time to response (TTR) defined as the time between date of randomization and first documented response (CR or PR), in the subset of subjects classified as responders in the assessment of ORR.
Measure:Duration of Response (DoR) - Phase 2 part
Time Frame:At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
Safety Issue:
Description:Phase 2 part: Duration of Response (DoR) defined as the time, in days, from the first recorded achievement of a response (PR or above) until time of objective disease progression in the subset of subjects classified as responders in the assessment of ORR.
Measure:Disease Control Rate (DCR) - Phase 2 part
Time Frame:At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
Safety Issue:
Description:Phase 2 part: Disease Control Rate (DCR) defined as the proportion of subjects with a (BOR of CR or PR, or SD maintained for a minimum of twelve weeks (-5 days) from randomization, as defined by the RECIST v1.1 criteria.
Measure:Overall Survival (OS) - Phase 2 part
Time Frame:From randomization to end of study (Last subject last visit (LSLV)) (up to approximately 24 months)
Safety Issue:
Description:Phase 2 part: Overall Survival (OS) defined as the time from randomization until death by any cause. Any subject not known to have died at the time of the analysis will be censored based on the last recorded date on which the subject was known to be alive.
Measure:Pharmacokinetic: area under the plasma concentration time curve (AUC) from 0 to 6 hours (AUC0-6) - Phase 2 part
Time Frame:Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
Safety Issue:
Description:Phase 2 part: Pharmacokinetic of Varlitinib
Measure:Pharmacokinetic: maximum observed plasma concentration (Cmax) - Phase 2 part
Time Frame:Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
Safety Issue:
Description:Phase 2 part: Pharmacokinetic of Varlitinib
Measure:Pharmacokinetic: time to Cmax (tmax) - Phase 2 part
Time Frame:Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
Safety Issue:
Description:Phase 2 part: Pharmacokinetic of Varlitinib
Measure:Pharmacokinetic: accumulation ratio for AUC (Rac AUC0-6) - Phase 2 part
Time Frame:Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
Safety Issue:
Description:Phase 2 part: Pharmacokinetic of Varlitinib
Measure:Pharmacokinetic: accumulation ratio for Cmax (Rac Cmax) - Phase 2 part
Time Frame:Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
Safety Issue:
Description:Phase 2 part: Pharmacokinetic of Varlitinib
Measure:Objective Response Rate (ORR) - Phase 3 part
Time Frame:When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
Safety Issue:
Description:Phase 3 part: Objective Response Rate (ORR) defined as the proportion of subjects with a best objective response (BOR) of complete response (CR) or partial response (PR), as defined by the RECIST v1.1 criteria.
Measure:Progression-free survival (PFS) - Phase 3 part
Time Frame:When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
Safety Issue:
Description:Phase 3 part: Progression-free survival (PFS) defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of disease progression), whichever comes first. Progression is defined in accordance with the RECIST v1.1 criteria.
Measure:Time to response (TTR) - Phase 3 part
Time Frame:When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
Safety Issue:
Description:Phase 3 part: Time to response (TTR) defined as the time between date of randomization and first documented response (CR or PR), in the subset of subjects classified as responders in the assessment of ORR.
Measure:Duration of Response (DoR) - Phase 3 part
Time Frame:When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
Safety Issue:
Description:Phase 3 part: Duration of Response (DoR) defined as the time, in days, from the first recorded achievement of a response (PR or above) until time of objective disease progression in the subset of subjects classified as responders in the assessment of ORR.
Measure:Disease Control Rate (DCR) - Phase 3 part
Time Frame:When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
Safety Issue:
Description:Phase 3 part: Disease Control Rate (DCR) defined as the proportion of subjects with a (BOR of CR or PR, or SD maintained for a minimum of twelve weeks (-5 days) from randomization, as defined by the RECIST v1.1 criteria.
Measure:Incidence of Adverse Events (AEs) - Phase 3 part
Time Frame:When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
Safety Issue:
Description:Phase 3 part: Incidence of AEs, categorized in accordance to CTCAE 4.03 and changes from baseline in safety parameters (including vital signs, ECG parameters, clinical laboratory tests)
Measure:Health-related quality of life (QoL) - Phase 3 part
Time Frame:When 247 OS events have occured. 247 OS is estimated to occur after approximately 45 months
Safety Issue:
Description:QLQ-C30 and EORTC QLQ-STO22 questionnaire
Measure:European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30) measuring patients general cancer symptoms and functioning - Phase 3 part
Time Frame:When 247 OS events have occured. 247 OS is estimated to occur after approximately 45 months
Safety Issue:
Description:Phase 3 part: To assess on disease-related symptoms and health-related quality of life (QoL) of gastric cancer patients
Measure:European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Gastric Cancer 22 items (EORTC QLQ STO22) measuring patients general cancer symptoms and functioning - Phase 3 part
Time Frame:When 247 OS events have occured. 247 OS is estimated to occur after approximately 45 months
Safety Issue:
Description:Phase 3 part: To assess on disease-related symptoms and health-related quality of life (QoL) of gastric cancer patients

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Aslan Pharmaceuticals

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